Vitamin D and Risk of Death From Vascular and Non-Vascular Causes in the Whitehall Study and Meta-Analyses of 12,000 Deaths

Study Questions:

Are 25-hydroxyvitamin D [25(OH)D] levels associated with risk for vascular and nonvascular mortality?

Methods:

Data from the Whitehall study, a prospective study of 19,019 male civil servants (working in London), were used for the present study. Of those recruited between 1967 and 1970, surviving participants (n = 8,448) were resurveyed in 1997-1980. Of those who responded, a lab sample was requested; 5,409 provided this blood sample, from which 25(OH)D levels were measured. The primary outcomes of interest were vascular and nonvascular mortality. For the meta-analysis, all published reports from prospective studies (including the Whitehall study), which reported associations of 25(OH)D levels with either vascular mortality or all-cause mortality before January 2012, were included. Studies were excluded if they were selected on the basis of diagnosis of prior disease (cancer, vascular, or renal disease); risk factors (diabetes and hypertension); or inclusion of nursing home residents and/or participants in clinical trials.

Results:

A total of 5,409 men were included in this study (mean age 76.9 years). Approximately one-third (1,841 men) had a history of prior vascular disease, cancer, or diabetes at time of the repeat survey (1997-1980). The majority (87%) were nonsmokers, whereas 78% were self-reported alcohol drinkers. Median 25(OH)D concentration (standardized for month of blood collection) was 56 nmol/L (interquartile range, 45-67 nmol/L). Men with higher 25(OH)D also had lower mean body mass index and were less likely to have been of manual/clerical grade at retirement compared to men with lower 25(OH)D. In contrast, men with higher plasma 25(OH)D concentrations had higher mean low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, ApoA1, and albumin concentrations, and lower mean C-reactive protein and fibrinogen concentrations, than men with lower 25(OH)D concentrations. In a 13-year follow-up, 1,358 died from vascular and 1,857 from nonvascular causes. After adjustment for age and season, higher concentrations of 25(OH)D were inversely associated with vascular and nonvascular mortality. After additional adjustment for prior disease and cardiovascular risk factors, a doubling in 25(OH)D concentration was associated with 20% (95% confidence interval [CI], 9-30%) lower vascular and 23% (95% CI, 14-31%) lower nonvascular mortality. The meta-analyses (which included results from the current study) included 12 prospective studies with 4,632 vascular deaths, and 18 prospective studies with 11,734 deaths from all causes. Participants with a 25(OH)D concentration in the top versus bottom quarter of distribution had on average 21% (95% CI, 13-28%) lower vascular mortality and 28% (95% CI, 24-32%) lower total mortality.

Conclusions:

The investigators concluded that 25(OH)D was inversely associated with vascular and nonvascular mortality.

Perspective:

These results added to prior studies suggesting that vitamin D is inversely associated with vascular risk. However, as the authors suggest, information from ongoing randomized trials will address the question of whether vitamin D supplementation results in reduced risk for cardiovascular disease.